Effects of prenatal protein malnutrition on kindling-induced alterations in dentate granule cell excitability: I. Synaptic transmission measures

Abstract

The effects of prenatal protein malnutrition upon the efficacy of excitatory synaptic transmission at the level of the perforant path/dentate granule cell synapse were examined during development of perforant path kindling in chronically implanted adults rats. Rats born to dams fed a low protein (6% casein) or control protein (25% casein) diet were fostered to lactating dams fed the 25% casein diet 24 h after birth and were maintained on this diet throughout life following weaning. Beginning at 90–120 days of age, animals received daily kindling stimulations applied to the perforant path. Extracellular field potentials recorded from the granule cell layer of the dentate gyrus in response to single-pulse stimulation of the perforant path were analyzed to determine the effects of prenatal protein malnutrition on the efficacy of synaptic transmission during the kindling process. Measures used for these analyses included the EPSP slope, an indicator of the level of synaptic drive, the population spike amplitude which is a measure of postsynaptic activation and cellular firing, and the ratio of the population spike amplitude relative to the corresponding EPSP slope value, which was used to evaluate the overall efficacy of synaptic transmission. Animals of the 6% 25% diet group were found to have significantly lower afterdischarge thresholds, yet required significantly more daily kindling stimulations to develop generalized motor convulsions (stage 5 seizure) than control animals. Examination of dentate field potentials obtained prior to kindling revealed no significant between group differences in measures of EPSP slope or population spike amplitude. Statistically significant increases in measures of both the population EPSP slope and population spike amplitude were observed in both diet groups 24 h after the first kindled afterdischarge. The degree of increase in both of these measures was significantly greater in animals of the 6% 25% group. Evaluation of input/output measures obtained during kindling revealed a steady increase in the population EPSP slope for both diet groups with animals of the 6% 25% group showing significantly greater levels of enhancement in this measure than controls. Enhancement of population spike amplitudes reached maximal values in animals of the 25% 25% group within the first few kindling stimulations and these levels remained unchanged until the first stage 5 seizure. In contrast, animals of the 6% 25% group showed a continuous increase in the population spike amplitude measure during the entire kindling process. Appearance of the first generalized motor convulsion (stage 5 seizure) resulted in a decrease in population spike amplitudes in both diet groups, with animals of the 6% 25% group showing a significantly greater decrease in this measure than controls. Significant decreases in population EPSP slope measures following stage 5 seizure were observed only in 6% 25% animals. These findings suggest that the greater levels of enhanced excitatory synaptic transmission seen in animals of the 6% 25% diet group may underlie the increased seizure susceptibility as reflected in lower afterdischarge thresholds in this group. In the following paper we report that a significant enhancement of inhibition of granule cell activity accompanies kindling in 6% 25% animals, suggesting that an LTP-like effect resulting in enhancement of dentate inhibitory activity may underlie the delayed evolution of behavioral manifestations of seizure in animals of the 6% 25% diet group. Results of these studies indicate that dietary protein rehabilitation instituted at birth is incapable of reversing the effects of gestational protein malnutrition and suggest that gestational protein deficiency results in long-lasting, if not permanent, changes in response properties of neuronal system involved in both the electrographic and behavioral correlates of the kindling process.